PROJECT SUMMARY. There is a fundamental gap in understanding the mechanisms underlying the development of pediatric neuropsychiatric systemic lupus erythematosus (pNPSLE), especially pertaining to neurocognitive dysfunction (NCD), and no effective screening tools to help diagnose NCD in children with pediatric SLE (pSLE) are available. This is an important problem because NCD is common among children with pSLE, often resulting in a pervasive decline in attention, visuoconstructional ability and working memory. The long-term goal of our research is to improve the prognosis of children with pSLE through better evidence-based treatments. The objectives of this application are to make an easy-to-use screening tool for NCD available for use in routine clinic settings and to employ advanced imaging techniques to heighten our understanding in how pSLE affects the central nervous system and causes NCD. The central hypotheses to be tested are that pSLE is associated with impaired cognitive growth as reflected by changes in the grey matter functioning detected by functional magnetic resonance imaging (fMRI), alterations of white brain matter tracts seen with Diffusion Tensor Imaging (DTI), and confirmed by formal neuropsychological testing. Additionally, we hypothesize that the Pediatric Automated Neuropsychological Assessment Metrics (Ped-ANAM) has superior measurement properties for the early detection of pSLE-associated NCD over other available self-administered questionnaires of behavior, cognition and executive functioning. Guided by strong preliminary data, these hypotheses will be tested by pursuing the following specific aims: 1) Validate the Ped-ANAM as a measure of cognitive function in pSLE using formal neuropsychological testing as the criterion standard 2) Assess the effects of pSLE on cognitive development during childhood based on formal neuropsychological testing and the Ped-ANAM 3a) Use fMRI to identify grey matter elements of cognitive networks involved in attention, visuoconstructional ability & working memory that are most affected by pSLE; and 3b) Use DTI to estimate white matter changes involved in attention, visuoconstructional ability & working memory that are most affected by pSLE. Forty pSLE subjects and 40 matched 'best-friend' controls will be studied for 1.5 years using the Ped-ANAM and other validated neuropsychological tests. Advanced imaging will be done (fMRI, DTI) with focus on the two most commonly affected neurocognitive domains afflicted by pSLE. The proposed research is innovative, because there are no effective screening tools for pSLE-associated NCD that can be used by clinicians or researchers, and mechanisms leading to NCD and the specific effects of pSLE on the developing brain remain elusive. The expected results are that we will identify grey matter neuronal circuitries and white matter tracts that are associated with pSLE-associated NCD and that the prospective validation of the Ped-ANAM will yield a readily usable screening tool for pSLE-associated NCD. Relevance to Public Health: This is an important and underinvestigated field of investigation as pNPSLE worsens patient morbidity and mortality and decreases patient quality of life. Better diagnostic tests and knowledge about the pathoetiology of NCD is the basis for the future development of targeted therapies for children with pSLE and can likely also be used for adults with SLE.